Benzenesulfonyl ureas



United States Patent 3,409,644 BENZENESULFONYL UREAS Gerhard Muller and Rudolf Merten, Leverkusen, and Sophie Wirtz, Wuppertal-Elberfeld, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed June 24, 1965, Ser. No. 466,821 'Claims priority, application Germany, June 30, 1964, F 43,301 7 Claims. (Cl. 260-397.7)

ABSTRACT OF THE DISCLOSURE Benzenesulfonyl ureas, and physiologically tolerable salts thereof, having the formula -s OzNHC ONH-Nortricyclyl R The present invention relates to benzenesulfonyl ureas of the general formula 35 which as such or in the form of their salts possess hypoglycemic properties and, as regards activity, are far superior to the known N-(4-methyl-benzenesulfonyl)-N- n-butyl-urea.

In the above formula R and R halogen, alkoxy, acyl or an aliphatic urated hydrocarbon radical which may represent hydrogen, saturated or unsatbe substituted by R not representlng an amino group or an acylated amino group, R and R may be equal or different.

In the above and the following definitions, alky or alkoxy contain 1 to 4 carbon atoms in straight or branched chain. represents an acyl group (orradical of a corresponding length of chain.

R and 'R may represent, for instance, methyl, ethyl,

3,409,644 Patented Nov. 5, 1968 (a) reacting R, R'-substituted benzenesulfonyl-isocyanates, benzenesultonyl-carbamic acid esters, benzenesulfonyl-thiocarbamic acid esters, benzenesulfonyl-carbamic acid halides or benzenesulfonyI-ureas with aminonortricyclene or its salts;

(b) reacting benzenesulfamides of the formula R! or-if desiredtheir salts with nortricyclyl-isocyanate, nortricyclyl-carbamic acid esters, nortricyclyl-thiocarbamic acid esters, nortricyclyl-carbamic acid halides halides with nortricyclyl-urea, nortricyclyl-isourea ethers, no rtricyclyl-isothiourea ethers, dines or nort1icyclyl-parabanic acid or any other method; (e) replacing in correspondingly substituted benzenesulfonyl-thioureas the sulfur atom by an oxygen atom;

(f) oxidizing corresponding benzenesulfinyl-ureas or benzene sulfenyl-ureas and treating the products 'with alkaline agents if salt formation is desired.

According to the nature of the bridge members R and R, one or the other of the above-mentioned processes cyanates. It is known that masked isocyanates comprise, for instance, the reaction products of isocyanates with components which may relatively easily be split off again, e.g. by the action of heat, for instance with phenols, bisulfite, =malonic ester, s-caprolactam, a-pyrrolidone or compounds containing active methylene groups. As examples for benezenesulfonyl-isocyanates be mentioned: benzenesulfonyl-isocyanate, 4-, 3- and Z-methyl-benzenesulfonylisocyanates, 4-ethylbenzenesulfonyl-isocyanate, 4-methoxy-benzenesulfonyl-isocyanate, 2-, 3- and 4-chlorobenzenesulfonyl isocyanates, 4 acetylbenzenesulfonyl isocyanate.

Instead of nortricyclyl-isocyanate, it is generally also possible to utilize, in the same manner, compounds which react like nortricyclyl-isocyanate, in particular likewise so-called masked isocyanates.

A variation in the reaction of isocyanates with benzenesulfonamides is given by the reaction mentioned (sub 0) The above-mentioned benzenesulfonyl-carbamic acid esters or the benzenesulfonyl-thiocarb amic acid esters may contain in the alcohol component a low-molecular alkyl group or a phenyl group. The same applies to the nortricyclyl-cambarnic acid esters or the corresponding monothiocarbamic acid esters. In the sense of the invention there is to be understood by a low-molecular or a lower alkyl group in all cases an alkyl group containing not more than 4 carbon atoms. As examples for suitable benzenesulfonyl-carbamic acid esters or nortricyclyl-carbamic acid esters there are mentioned 4-methyl-benzenesulfonylmethyl-urethane, 4-methoxy-benzenesulfonyl-methyl-urethane, 4-n-propoxy-benzenesulfonyl-methyl-urethane, N- nortricyclyl-carbamic acid methyl ester, N-nortricyclylcarbamic acid isobutyl-ester and N-nortricyclyl-carbamic acid phenylester.

As carbamic acid halides, the chlorides are preferably suitable. There are mentioned, for instance, the 4-methylbenzenesulfonyl-carbamic acid chloride and the 4-chlorobenzenesulfonyl-carbamic acid chloride.

The benzenesulfonyl-ureas used as starting substances for the process of the present invention may be unsubstituted at the side of the urea-molecule opposite to the sulfonyl group or may be monoor disubstituted, preferably by lower alkyl groups or aryl groups. Instead of benzenesulfonyl-ureas substituted in the above-described manner there may likewise be used corresponding N-benzenesulfonyl-N'-acyl-ureas and bis-(benZenesulfonyl)-ureas. Thus is it possible, for instance, to treat bis-(benzene-sulfonyl)- ureas or N-benzenesulfonyl-N'-acyl-ureas with aminonortricyclene and to heat the salts obtained to elevated temperatures, partiularly above 100 C. As example of said ureas there are mentioned: 4-methyl-benzenesulfonylurea, 3-amino-4-methyl-benzene-sulfonyl-urea, N (4- methyl-benzenesulfonyl)-N'-acetyl-urea, N (4-methylbenzenesulfonyl)-N-propionyl-urea, N-(4-methyl-benzenesulfonyD-N,N'-diphenyl-urea or N,N-di(p-toluenesulfonyD-urea.

Furthermore, it is possible to start from N-nortricyclylureas or N-nortricyclyl-N-acyl-ureas wherein acyl preferably represents a low-molecular aliphatic or an aromatic acid radical or the nitro group, or from N-nortricyclyl-N'- phenyl-ureas or from N-nortricyclyl-N, N-diphenyl ureas in which the phenyl groups are substituted and linked together directly or by means of a bridge member such as -CH NH-, -O- or -S- or from N, N'-dinortricyc1yl-urea an to react these with R,R-substituted benzene-sulfonamides. As examples for said benezene-sulfonarnides there are mentioned: benzene-sulfonic acid amide, 2-methyl-benzenesulfonic acid amide, 3- methyl-benzene-sulfonic acid amide, and 4-methyl-ben zenesulfonic acid amide, 2-chlorobenzenesulfonic acid amide, 4-chlorobenzene-sulfonic acid amide, 4-acetyland 4-methoxy-benzenesulfonic acid amide, 3-amino-4-methylbenzenesulfonie acid amide, 4-(a-hydroxyethyD-benzenesulfonic acid amide. As examples for suitable nortricyclylureas there are mentioned: N-nortricyclyl-N'-acetyl-urea, N-nortricyclyl-N-propionyl-urea, N-nortricyclyl-N'-N'- diphenyl-urea.

As an example for the reaction mentioned (sub d) the reaction of a nortricyclyl-isourea-alkyl ether with a benzenesulfonic acid chloride is demonstrated. The benzenesulfonyl-isourea ether can then be split into an alkylhalide and the desired benzenesulfonyl-urea by treatment with a hydrohalic acid. Other derivatives of carbonic acid can likewise be used as starting substances and an undesired radical present therein can hydrolytically be replaced by oxygen or can be converted by another operation, for instance by oxidization, into oxygen. The following. scheme shows an example for the conversion of a guanidine, for instance, by alkaline hydrolysis in order to obtain the desired sulfonyl-urea.

De -c mm The sulfur atom can be replaced by an oxygen atom'in the correspondingly substituted benzenesulfonyl-thioureas for instance with the aid of oxides or salts of heavy metals or by applying oxidizing agents such as hydrogen-peroxide, sodiumperoxide or nitrous acid.

The thio-ureas can likewise be desulfurized by treating them with phosgene or phosphorus pentachloride. Chloroformic acid amidines or carbodiimides obtained as'intermediate products can be converted by suitable measures such as hydrolysis or addition of water, into the benzenesulfonyl-ureas.

In the same manner as the benzenesulfonyl-thioureas, the benzenesulfonyl-isothiourea-ethers which in the sense of the invention are equal to the benzenesulfonylthioureas, can be desulfurized.

Generally, the methods of realizing the process according to the invention may vary within wide limits as regards the reaction conditions and can be adapted to each individual case. For instance, the reactions can be carried out with the use of solvents, at room temperature or at an elevated temperature. As solvents there may be mentioned inert aromatic hydrocarbons such as toluene, xylene, chlorobenzene, dichlorobenzene, furthermore certain polar solvents such as dimethylformamide, dimethyl-sulfoxide, dioxide, acetone, furthermore glycolmonornethyl ethers or their mixtures. In order to obtain the compounds prepared according to the process of the present invention in a form as pure as possible they are suitably dissolved and reprecipitated. Thus the crude product can be dissolved in dilute ammonia, benzenesulfonamides formed in the course of the reaction are filtered olf and the filtrate is acidified. The products of the invention can be recrystallized from appropriate solvents such as dilute alcohols.

The compounds obtained according to the process of the present invention are characterized by a strong hypoglycemic action. In order to examine the hypoglycemic action, a product obtained according to the present invention, viz. N-(4-methylbenzenesulfonyl)-N-nortricyclylurea, was given to starved dogs with normal metabolism in the indicated dose in the form of a tragacanth suspension by means of the esophageal sound. Blood was first taken shortly before the application in order to determine the blood sugar value of the starved animal; further blood samples were taken each hour from the vein of the leg of the dogs. The blood-sugar values were determined according to the method of Hagedorn-Iensen.

In the following table the reductions of the blood sugar values are indicated in percent of the initial value and, for comparisoin, the reductions attained under equal test conditions with N-(4-methyl-benzenesu1fonyl)-N'-n-butylurea are likewise indicated.

The products of the invention are to be used preferably as orally administerable preparations showing hypo glycemic action in the treatment of diabetes mellitus. They can be applied as such or in the form of their salts or in the presence of substances causing salt formation. For the salt-formation there can be used: alkali metals such as alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, ammonia, further-more, physiologically tolerable organic bases. They are applied preferably in the form of tablets containing in addition to the products of the invention the usual auxiliary and carrier substances 6 such as talc, starch, lactose, tragacanth, magnesium filtrate is adjusted to a pH-value of 5.2 to 50 C. by stearate. means of hydrochloric acid of 10% strength. A crystal- Blood sugar reduction in starved dogs showing normal metabolism Oral Value obtained Percent of reduction referred to the initial Animal Number Administered preparation dose, with starved value after hours mgJkg. animal, mg.

percent 1 2 3 4 5 6 N-(4-methylbenzene)-N-nortricyclyl-urea 5 91 19 19 23 23 18 19 2 .do 5 88 20 26 30 26 22 18 R Average values (19.5) (22.5) (26.5) (24. 5) (20) (18.5) 3 N-(4-methylbenzene)-N-nortricyclyl-urea 2.5 90 17 26 29 22 9 8 4 .410 2. 5 9o 20 24 26 19 10 10 Average values (18. 5) (25) (27. 5) (20.5) (9.5) (9) 5 N-(4-methylbenzene)-Nn-butyl-urca 5 90 7 11 16 9 6 6 ..d0 5 88 13 14 11 s 6 6 Average values (10) (12.5) (13.5) (11.5) (7.5) (6) 7 N(4-methylbenzcne)-Nn-butyl-urea 2.5 90 9 14 12 11 7 9 s ..d0 2.5 91 a 11 9 8 5 5 Average values (6) (12.5) (10.5) (9.5) (6) The following examples serve to illustrate the invenline precipitate of N-(p-amino-benzenesulfonyl)-N-nortion but are not intended to limit it thereto; the parts are tricyclyl-urea is formed. Yield 24 parts. Melting point by weight. 204-206 C.

Example 1 25 Example 4 To a solution of 67 parts of p-toluenesulfonic acid To a solution of 39 parts of p-acetyl-benzenesulfonic amide and 15.5 parts of sodium-hydroxide in 150 parts acid amide and 8 parts of sodium-hydroxide in 125 parts of Water and 120 parts of acetone, 55 parts of norttri of water and 100 parts of acetone, 27.5 parts of nortricyclyl-isocyanate are added dropwise with cooling to cyclyl-isocyanate are added dropwise While cooling to +10 C. The reaction mixture is allowed to react for 3 +10 C. The reaction is continued for a further 3 hours hours at room temperature, it is filtered and the filtrate at room temperature, the substance is worked up as deis acidified by means of acetic acid. A crystalline prodscribed in Example 1 and 20 parts of N-(p-acetyl-benuct is precipitated which is filtered with suction, washed zenesulfonyl) N norticyclyl-urea are obtained which with water and dried under reduced pressure. The N-(4- melts at 168 C. and is clearly soluble in dilute ammonia. methyl-benzenesulfonyl)-N'-n0rtricyclyl-urea is obtained We claim: in a quantity of 101 grams. Melting point 200 C. 1. A benzenesulfonyl-urea of the formula Example 2 To a solution of 30.5 parts of benzenesulfonic acid 40 amide and 8 parts of sodium-hydroxide in 75 parts of R 2 Nix-Comm- Water and 60 parts of acetone, 27.5 parts of nortricyclylisocyanate. are afided dfopwlse with cooling to +10 in which R is hydrogen, halogen, lower alkyl, lower alk- The reaction mixture is allowed further to react for 3 oxy acetyl, propionyl, benzoyl, halo lower alkyl, amino i lower alkyl, hydroxy-lower alkyl, lower alkenyl, halohours at room temperature, it is worked up as described in Example 1 and after recrystallization from n-propanol lower alkenyl amino lower alkenyl or hydroxy lower g j' ggg g N n'ortricyclyhurea is obtained alkenyl and R is hydrogen, halogen, lower alkyl, lower w me ts atz alkoxy, acetyl, propionyl, benzoyl, halo-lower alkyl, Example 3 amino-lower alkyl, hydroxy-lower alkyl, lower alkenyl,

halo-lower alkenyl, amino-lower alkenyl, hydroxy-lower alkenyl, amino, acetylamino, propionylamino or benzoyl- 75 parts of water and 60 parts of acetone, 27.5 parts of nortricy clyl-isocyanate are added dropwise while cooling to +10 C. The mixture is allowed further to react for 4. A physiologically tolerable salt with a base of a 3 hours at room temperature, it is Worked up as described in Example 1 and the N-(p-acetyl-amino-benzenesulfonyl)-N'-nortricyclyl-urea is obtained in a quantity of 56 parts. Melting point 228 C. The reaction product is clearly soluble in dilute ammonia. 34 parts of the compound as claimed in claim 1.

5. N-benzenesulfonyl-N'-nortricyclyl urea. 6. N-(p-amino-benzenesulfonyl)-N'-n0rtricyclyl urea. 7. N- (p-acetyl-benzenesulfonyl -N'-nortricyclyl urea.

60 N (p-acetylammo-benzenesulfonyl)-N-nortr1cyclyl-urea d are heated with 60 parts of 5 N-potassium hydroxide so- References Cue lution for 70 minutes in the water bath of 92 C., while UNITED STATES PATENTS stirring. A rigid crystalline cake is formed which is dl'S- 3,096,372 7/1963 Gerzon 260-553 solution is shaken with charcoal and then filtered. The JOHN D. RANDOLPH, Primary Examiner. 

